The long-term objective of the proposed research is to improve understanding of the responses of normal tissues to irradiation with a view to increasing the therapeutic index in radiotherapy. The effect of regeneration by surviving clonogenic cells during treatment, and of repair of sublethal injury on responses to multiple fractions wil be evaluatedd separately. Specifically, the aims are to: 1. Determine the dose survival characteristics of renal tubule cells over a dose range of 100-1600 rad and to measure the kinetics of repair of sublethal injury and of regeneration during fractionated radiotherapy. The pattern and rate of decay of radiation injury over weeks and months will be studied. 2. Elucidate the mechanisms underlying the different dose fractionation responses of acutely- and slowly-responding tissues through investigations of the dose survival characteristics of renal tubule cells and of hair follicle cells under different conditions of proliferation. 3. Determine the times of onset and rates of regeneration of the cells in various normal tissues (jejunum, colon, hair, kidney) as a function of fraction size and fractionation interval). 4. Measure the cytotoxicity of certain chemotherapy drugs to cells of the gastrointestinal mucosa and of the renal tubules using cell cloning endpoints in situ. 5. Measure the cytotoxicity to renal tubule cells of hyperthermia alone or combined with irradiation or chemotherapy. 6. Measure X ray dose survival characteristics for melanoblasts in the hair follicle over the dose range 50-400 rad.